Asp-53(H) is positioned by Ser-52(H) and Thr-55(H) and a water molecule that bridges the CDRH2 and CDRH3 loops. on multiple pathogens. Keywords:germline antibody, human cytomegalovirus, immunological memory, structure, thermodynamics == Introduction == Human cytomegalovirus (HCMV) is a member of the family Herpesviridae that also includes herpes simplex virus and EpsteinBarr virus. HCMV co-evolved with humans (McGeochet al, 2000) and although 5090% of humans are chronically infected with HCMV, it rarely causes harm because it is kept in check by the immune system. However, HCMV can cause serious and sometimes fatal disease (retinitis, pneumonitis and hepatitis) in adults who are immunocompromised by AIDS or immunosuppressive drugs. Moreover, about 1% of susceptible women acquire a primary infection during pregnancy, with 40% of these women transmitting CMV to their fetuses, often causing death or severe neurological defects (Boppanaet al, 1992;Duff, 2005). No protective vaccine is currently available. Recent evidence indicates that the administration of pooled human immunoglobulins (that contain antibodies that neutralize HCMV) reduces the incidence of congenital abnormalities in neonates born to mothers who suffer from primary HCMV infections during Iproniazid phosphate pregnancy (Nigroet al, 2005). HCMV can be neutralized by antibodies that target Iproniazid phosphate a short, linear epitope on the gB envelope protein of HCMV termed AD-2S1 (amino-acid sequence: ETIYNTTLKY), which is thought to serve an important function in viral infectivity (Meyeret al, 1990;Ohizumiet al, 1992). Intriguingly, although the three different families of human antibodies specific for AD-2S1, for which sequences are available, were independently derived from two unrelated individuals, all were derived from the same pair of V-genes (IGHV3-30andIGKV3-11) (Ohlinet al, 1993;McLeanet al, 2005). Similarly, a fourth family of heavy chain sequences of anti-AD-2S1 antibodies were analysed from a third individual and found to use the same VH gene (IGHV3-30) (McLeanet al, 2005). On the basis of the frequency of use of these V-genes in human B lymphoid cells (0.048 and 0.12, respectively) (Lefrancet al, 2005), the probability that this pair of V-genes was used by chance in these three independently generated sets of anti-AD-2S1 antibodies is vanishingly small (0.0000002). Rather the consecutive use of this pair of V-genes suggests that this pair of V-genes make critical contributions to encoding a preferred binding site for AD-2S1. This is consistent with other evidence for the preferential use of V-genes in antibodies against haptens (Makela and Kaartinen, 1988). However, the fact that the AD-2S1 epitope is the target of antibodies that block infectivity with a common pathogen raises the possibility that these V-genes have undergone evolutionary selection to facilitate the generation of a binding site for this epitope. Immunoglobulin genes represent the largest and most diverse class of genes in any organism. Throughout life, random pairs of novel heavy and light chain immunoglobulin genes are assembled in each newly generated B lymphocyte. The immunoglobulin H- and L-chain genes each encode Iproniazid phosphate three of the six variable complementarity determining regions’ (CDRs) that make up the antigen-combining site of immunoglobulins. The amino-acid sequences of these CDRs are extremely variable, accounting for the structural diversity of the KBTBD7 antigen-combining sites of immunoglobulins and their enormous repertoire of binding specificities. Further combinatorial diversity is generated by variation in the precise sites at which recombination occurs, as well as by the addition of untemplated Iproniazid phosphate bases at sites of recombination by the enzyme terminal deoxynucleotidyl transferase (TdT) (Desiderioet al, 1984;Thaiet al, 2002). The V-genes encode the N-terminal portion of their respective H- or L-chains, including CDR1, CDR2 and part of CDR3. The remaining parts of the CDR3s are encoded by somatically generated DNA.